Studying a Cancer-Causing Virus

Research is revealing how KSHV infection in the mouth might progress to cancer

Kaposi's sarcoma cells (Source: National Cancer Institute)

Infection with a virus known as KSHV (also called Kaposi’s sarcoma herpesvirus, human herpesvirus-8, or HHV8) can cause Kaposi’s sarcoma, a cancer characterized by red or brownish purple growths in the mouth, on the skin, or elsewhere. In two recently published articles, NIDCR-supported scientists revealed details about mechanisms that may increase KSHV’s ability to cause Kaposi’s sarcoma in the mouth. The ultimate goal of such research is to prevent or treat Kaposi’s sarcoma by turning off specific KSHV genes.

In most healthy adults, KSHV establishes a latent infection, evading detection and destruction by the person’s immune system, and persisting without causing cancer. However, under certain conditions, such as in a person with an impaired immune system, replication of the virus is no longer repressed, genes are turned on, and KSHV infection transitions from latency to active replication. In the replication phase, KSHV kills the cell that it infected and releases progeny viruses into the body to infect other cells.

For many people with an impaired immune system, KSHV shows enhanced expression of its cancer-causing genes, increasing the chance that Kaposi’s sarcoma or other cancers will develop. The enhanced expression of cancer-causing genes explains why people with an impaired immune system — such as those infected with HIV (human immunodeficiency virus, the cause of AIDS) — are more likely to be diagnosed with Kaposi’s sarcoma.

Kaposi's sarcoma in the mouth of man with HIV/AIDS (Source: National Cancer Institute)

Certain fatty acids made by bacteria induce KSHV replication

NIDCR-supported scientists at Case Western Reserve University examined the mechanisms that could induce the latent KSHV to activate genes that enable replication. They reported in the Journal of Virology that certain fatty acids made by the bacteria that cause periodontal disease could influence viral gene expression in KSHV-infected oral cells so that the virus shifted from latency to replication. Their results suggested that periodontal disease results in the release of certain bacteria-derived fatty acids in the mouth that could enhance KSHV infectivity and increase the risk of developing oral Kaposi’s sarcoma in people with HIV/AIDS.

The infected cells have certain protective mechanisms that keep the KSHV infection in check during latency. One of these cellular regulatory mechanisms involves a group of enzymes known as histone deacetylases, which prevent the genes needed for virus replication from being turned on. The researchers showed that certain bacteria-derived fatty acids can induce KSHV replication by removing the silencing factor of histone deacetylases and by simultaneously turning off many cellular regulatory mechanisms that keep KSHV in latency. Further defining the mechanisms for how fatty acids or other factors enable KSHV to express its genes for replication could lead to the discovery of novel therapies to prevent and treat KSHV-driven cancer.

KSHV genetic material changes shape inside the cell

NIDCR-supported researchers at University of Southern California’s Keck School of Medicine are studying what drives KSHV latency and replication. After KSHV infects the cell, its DNA changes its structure from a linear form to a protective, closed circle. The circle of viral genes becomes covered with stabilizing proteins (histones) that are like beads on the necklace of genetic material. The latent phase of KSHV infection depends on the KSHV genetic material acquiring the compact shape of the stabilized circle.

The Keck School of Medicine researchers reported in PLoS Pathogens that the KSHV stabilized circle goes through two modifications after infection: the first form permits replication and the second form is associated with the latency phase. In addition, they identified the key molecules that turn off the genes for KSHV replication.

The researchers also discovered that the type of cell that KSHV infects may determine whether latency or replication is more likely. Cells that line the mouth (oral epithelial cells, especially cells in the gum tissue) are more likely than most other cell types to support KSHV replication and the progression to disease. By identifying characteristics of oral cells that make them more susceptible to KSHV replication, researchers may be able to devise methods to prevent disease.